68Ga-DOTATATE PET/CT versus 111In-octreotide scintigraphy in patients with neuroendocrine tumors: a prospective study

Objective To compare 68Ga-DOTA-DPhe1,Tyr3-octreotate (68Ga-DOTATATE) positron-emission tomography/computed tomography (PET/CT) findings with those of conventional 111In-octreotide scintigraphy in patients with neuroendocrine tumors (NETs). Materials and Methods This was a single-center prospective study including 41 patients (25 males; mean age, 55.4 years) with biopsy-proven NETs who underwent whole-body 111In-octreotide scintigraphy and whole-body 68Ga-DOTATATE PET/CT. The patients had been referred for tumor staging (34.1%), tumor restaging (61.0%), or response evaluation (4.9%). Images were compared in a patient-by-patient analysis to identify additional lesions, and we attempted to determine the impact that discordant findings had on treatment planning. Results Compared with 111In-octreotide scintigraphy, 68Ga-DOTATATE PET/CT revealed more lesions, the additional lesions typically being in the liver or bowel. Changes in management owing to the additional information provided by 68Ga-DOTATATE PET/CT occurred in five patients (12.2%), including intermodal changes in three (7.3%) and intramodal changes in two (4.9%). In addition, 68Ga-DOTATATE PET/CT yielded incidental findings unrelated to the primary NET in three patients (7.3%): Hürthle cell carcinoma of the thyroid, bowel non-Hodgkin lymphoma, and a suspicious breast lesion. Conclusion We conclude that 68Ga-DOTATATE PET/CT is superior to conventional 111In-octreotide scintigraphy for the management of NETs because of its ability to determine the extent of the disease more accurately, which, in some cases, translates to changes in the treatment plan.


INTRODUCTION
Although neuroendocrine tumors (NETs) constitute a rare type of tumor, the rate of their detection has been by somatostatin receptor (SSTR) overexpression. The treatment of a NET should be individualized and often requires a multimodal approach, which may include some combination of surgery, molecularly targeted therapy, chemotherapy, somatostatin analogue radiopharmaceutical therapy, ablation, and embolization. The localization of primary tumors and detection of metastatic lesions are essential to proper therapeutic planning (1)(2)(3) .
It is often difficult to locate NETs by conventional imaging because of their small size, multiplicity, and presence in the gastrointestinal tract. In recent decades, scintigraphy with 111 In-radiolabeled somatostatin analogues has proven to be an effective diagnostic imaging method for the detection of well-differentiated NETs.
The introduction of hybrid systems, such as singlephoton emission computed tomography/computed tomography (SPECT/CT) has improved the localization of lesions identified by SSTR scintigraphy (SRS) with a somatostatin analogue. Although SPECT/CT shows high efficacy for whole-body imaging, it has limitations in organs with higher physiological uptake, such as the liver, and in the detection of small lesions due to the low spatial resolution of the method (4-8) .
The objective of the present study was to compare 68 Ga-DOTATATE PET/CT with conventional 111 In-octreotide SRS for lesion detection in patients diagnosed with a NET, as well as to evaluate its impact on treatment.

MATERIALS AND METHODS Patients
This was a cross-sectional, prospective, single-center study involving a sample of 41 consecutive patients (25 males and 16 females), with a mean age of 55.4 years (range, 24-86 years). All of the patients had a biopsyproven NET and underwent both 68 Ga-DOTATATE PET/ CT and conventional 111 In-octreotide SRS between April 2014 and October 2016. The study protocol was approved by the local institutional review board, and all participating patients gave written informed consent.

Image acquisition
All of the patients underwent conventional 111 In-octreotide SRS followed within 15 days by 68 Ga-DOTATATE PET/CT. Administration of short-acting octreotide or a long-acting somatostatin analogue was discontinued 10 and 30 days prior to scanning, respectively.
Conventional 111 In-octreotide SRS protocols included planar scans and SPECT/CT, when possible. Conventional 111 In-octreotide SRS was performed after intravenous administration of 185 MBq of 111 In-pentetreotide (OCT-IPEN; Instituto de Pesquisas Energéticas e Nucleares, São Paulo, Brazil). Images were acquired with a dual-head, large field-of-view gamma camera (Optima NM/CT 640; GE Healthcare, Milwaukee, WI, USA) equipped with a medium-energy collimator. Planar whole-body scans were acquired at 3-4 h and 24 h after radiopharmaceutical administration. Eight patients also underwent an abdominal SPECT/CT examination at 4 h after radiopharmaceutical administration.
Images were reconstructed iteratively based on the ordered subset expectation maximization algorithm. Transmission data obtained during CT were used for anatomical localization of scintigraphic findings. For the assessment of radiotracer uptake, 111 In-octreotide intensities of tumor foci were compared with physiological liver uptake intensities observed on a planar whole-body scan. The intensities seen on attenuation-corrected SPECT/CT were also taken into account.
All PET/CT scans were acquired in a fully 3-dimensional scanner (Gemini TF; Philips Medical Systems, Cleveland, OH, USA). The 68 Ga-DOTATATE was administered intravenously, scanning beginning 50-60 min after injection of 185 MBq of the radiotracer. The PET/CT protocol consisted of an unenhanced CT scan followed by a PET scan. The PET images were acquired from the top of the skull to the mid-thigh, with a 3-min bed positioning time and the patient lying supine with the arms down and extended. The PET images were corrected for tissue attenuation based on CT data, after which they were reconstructed by iterative reconstruction. The same images were then evaluated qualitatively and semi-quantitatively based on a standard uptake value, defined as the quotient of maximum activity concentration divided by the ratio between the injected dose (numerator) and the body weight of the patient.

Image analysis
The 68 Ga-DOTATATE PET/CT and 111 In-octreotide SRS images were reviewed and interpreted by two nuclear medicine physicians, working independently, each blinded to the other set of images and to other imaging modalities. Any area with an intensity greater than the background not attributable to physiological activity was considered suspicious for tumor tissue. The 68 Ga-DOT-ATATE PET/CT and conventional 111 In-octreotide SRS findings in each region were classified as concordant if the same foci were seen in that region on both modalities or discordant if foci were seen on only one modality. In cases of discrepancy, the images were reviewed by a third nuclear medicine physician. After individual patient analysis of the imaging findings, their effects on the treatment were assessed. Changes in management were further classified as intermodal (e.g., from surgery to systemic therapy) or intramodal (e.g., a change in the extent of surgery or in the chemotherapy regimen). The impact of imaging-study monitoring was classified as low, moderate, or high based on the complexity of the change in treatment proposed after the examination.

Data analysis
All analyses were performed with the IBM SPSS Statistics software package, version 20.0 (IBM Corp., Armonk, NY, USA). Categorical variables were reported as absolute and relative frequencies. Continuous variables were reported as means and standard deviations. Pearson chi-square tests with Yates correction or Fisher's exact tests were used in order to analyze case management changes in relation to categorical clinical variables. Values of p ≤ 0.05 were considered statistically significant.

RESULTS
The results of the 111 In-octreotide SRS and 68 Ga-DOT-ATATE PET/CT were concordant in 36 (87.8%) of the 41 patients evaluated, both being positive in 33 (80.5%) and both being negative in three (7.3%). The results were discordant in the five remaining patients (12.2%), all of whom had a positive PET/CT result and a negative SRS result, including three patients with liver metastases and two patients with pancreatic tumors. Among the 33 patients in which the results were positive in both modalities, 68 Ga-DOTATATE PET/CT revealed additional tumor sites in 11: in the bowel (n = 3); in lymph nodes (n = 2); in the liver (n = 1); in bone (n = 1); in the pancreas (n = 1); in the orbit (n = 1); in the breast (n = 1); and in the thyroid (n = 1). Images from an example case in which 68 Ga-DOTATATE PET/CT revealed additional tumors are shown in Figure  1. Overall, the 68 Ga-DOTATATE PET/CT imaging revealed more tumor sites than did 111 In-octreotide SRS. The locations of the lesions detected only by PET/CT were, in decreasing order, the liver, bowel, lymph nodes, bone, and pancreas (Table 1).
Changes in case management based on the additional information obtained by 68 Ga-DOTATATE PET/CT occurred in five (12.2%) of the 41 patients ( Table 2): inter-  modal changes (additional radiotherapy for an intraconal NET, surgery for a second primary pancreatic NET, or the introduction of bisphosphonates) in three; and intramodal changes (more extensive hepatectomy and the addition of hepatic nodulectomy) in two. Changes in management were not significantly related to age, gender, indication for the examination, tumor grade, primary tumor site, or prior treatment. The 68 Ga-DOTATATE PET/CT yielded incidental findings unrelated to the primary NET in three (7.3%) of the 41 patients. One patient was found to have a second primary thyroid tumor, which was confirmed postoperatively to be Hürthle cell carcinoma; one had bowel non-Hodgkin lymphoma, which was also confirmed postoperatively; and one had a suspected second primary breast tumor, which was confirmed by percutaneous biopsy to be a metastatic NET.

DISCUSSION
Our data demonstrate the superiority of 68 Ga-DOT-ATATE PET/CT over 111 In-octreotide SRS for the detection of NETs. Although most of the findings were concordant between the two methods, 68 Ga-DOTATATE PET/CT yielded additional findings that served to indicate changes in the treatment plan in 12.2% of the cases evaluated. Even when both modalities detected the same tumor sites, 68 Ga-DOTATATE PET/CT demonstrated the location of those sites with better precision and greater radiotracer uptake.
The present study expands upon previous reports demonstrating the superiority of 68 Ga-DOTATATE PET/ CT over SRS (including 111 In-octreotide SRS) and other conventional anatomical imaging modalities (CT and magnetic resonance imaging) for the evaluation of NETs. However, the detection of a greater number of lesions is not necessarily followed by a change in the disease staging or treatment plan (23) . Findings that may lead to changes in the treatment plan include the detection of previously unsuspected local recurrence or metastasis, the identification of occult primary tumors, and the confirmation of SSTR expression by tumors (11,23,24) . High-impact changes to the treatment plan include expanding the extent of the surgery planned, the addition of putatively curative resection of a NET of unknown origin, and the addition of systemic therapy due to detection of multiple metastases (25,26) .
Among the five cases in which 68 Ga-DOTATATE PET/ CT led to changes in the NET treatment plan in our sample, the changes were intermodal in three and intramodal in two. The rate at which a discordant result led to a change in the treatment plan was lower in the present study than in several previous studies, probably because of the high prevalence of patients with metastatic disease in our sample. The reported frequency of therapeutic changes varies widely in the literature, ranging from 4% to 83%, which reflects substantial heterogeneity across studies in terms of patient selection, methods, and the definition of changes to the treatment plan (10,21,(26)(27)(28) . Considering only studies in which PET/CT was performed after 111 In-octreotide scanning, one meta-analysis showed that changes in management were observed, on average, in 39% of patients (range, 16-71%), most (77%) being intermodal changes (12,(19)(20)(21)25) .
We observed another advantage of 68 Ga-DOTATATE PET-CT with respect to incidental findings unrelated to the primary NET, which has not commonly been described in the literature. In our sample, such findings included a thyroid nodule confirmed to be a second primary tumor (Hürthle cell carcinoma), a mesenteric mass confirmed to be a sign of synchronous lymphoproliferative disease (mantle lymphoma), and a small breast mass confirmed to be a NET metastasis after a primary breast tumor was ruled out.
Our study has some limitations. First, we investigated a heterogeneous group of patients in different stages of the Intermodal Change evolution of disease. However, this heterogeneity is representative of real-world clinical populations of patients undergoing 68 Ga-DOTATATE PET/CT. Second, we did not perform a lesion-by-lesion comparative analyses because not all patients were submitted to SPECT/CT studies during 111 In-octreotide SRS. That is a significant limitation because SPECT/CT images are more sensitive than are planar and SPECT images alone, as well as providing better anatomical correlation of the findings (29) . In addition, we evaluated only changes to the treatment plan that were prompted by discordant findings. The clinical oncology team accessing the data obtained from these diagnostic imaging studies made treatment decisions based on those findings together with other clinical observations, including previously collected morphological information, as has been the case in other studies (17,25,26) . Although 68 Ga-DOTATATE PET/CT is not as widely available as is 111 In-octreotide SRS, the costs of the two methods are comparable. Therefore, we believe that, over time, 68 Ga-DOTATATE PET/CT is likely to replace 111 In-octreotide SRS for the monitoring of patients with NETs. Together with 18 F-fluorodeoxyglucose PET/CT, 68 Ga-DOTATATE PET/CT can be used in order to assess heterogeneity of a NET noninvasively and to improve their individualized management (30,31) .
In conclusion, 68 Ga-DOTATATE PET/CT is clinically superior to 111 In-octreotide SRS for the management of NETs because of its ability to detect the extent of disease more accurately, which, in some cases, translates to changes in the treatment plan. In addition, 68 Ga-DOTATATE PET/ CT may improve patient care by yielding additional incidental findings. Our findings highlight the importance of incorporating this method into the routine evaluation of patients with NETs.